Prostaglandin f2 {62 {0 analogs

ABSTRACT

This invention is a group of new prostaglandin F analogs structurally similar to the natural prostaglandins F but differing therefrom in that the carboxy-terminated side chain of these new compounds contains more or fewer carbon atoms than the corresponding side chain of the natural prostaglandins F. These new prostaglandin F analogs are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, and labor induction at term.

United States Patent [191 Beahlll et a1.

1 1 Dec. 3, 1974 1 i PROSTAGLANDIN F2 B ANALOGS [75] Inventors: Philip E. Beal, Ill, Kalamazoo; Gunther S. Fonken, Charleston Township, Kalamazoo County; John E. Pike, Kalamazoo, all of Mich.

[731 Assignee: The Upjohn Company, Kalamazoo,

Mich.

[221 Filed: July 19, 1972 [211 App]. No.1 273,316

Related US. Application Data [63] Continuation-impart of Scr. No. 17,874, March 9, 1970, abandoned, which is a continuation-in-part of Ser, No 606,019, Dec. 30, 1966, abandoned, which is a continuation-in-part of Ser, No. 345,852, Feb. 19, 1964, Pat. No. 3,296,091.

[52] US. Cl 260/413, 260/211 R, 260/247.2 R, 260/268 R, 260/293.65, 260/326.3,

R, 260/468 D, 260/50l.1, 260/50115,

[51] Int. Cl. C07c 61/32, C07c 69/74 [58] Field of Search 260/514 D, 408 D, 408 Ca [56] References Cited UNlTED STATES PATENTS 3,706,789 12/1972 Bergstrom or al. 260/468 Primary ExaminerRobert Gerstl {57] ABSTRACT 2 Claims, N0 Drawings PROSTAGLANDIN F2 B ANALOGS CROSS REFERENCE TO RELATED APPLICATIONS DESCRIPTION OF THE INVENTION This invention relates to novel compositions of matter, and is more specifically concerned withnovel rganic compounds of the formula:

IIO

III

II OH I wherein R is hydrogen, alkyl of one to 8 carbon atoms, inclusive, or a pharmacologically acceptable cation, wherein a is zero or one, wherein n is 2, 3, 4, 5, 6, 7, or 8, wherein m is one, 2, 3, 4, or 5, and wherein indicates attachment of hydroxy to the ring in alpha or beta configuration with' the provisos that the compound contains l8, 19, 20, 2I, or 22 carbon atoms exclusive of R and that the chain does not contain 7 carbon atoms exclusive of R.

Included within the scope of formula I are compounds of the following formulas:

XVIII XIX XXI

II II (Ill; ((JIID UOOR ccuur cm u on 1|\ u XXIII no CL( 1 x Ull (Gim -000R n c Quorum u XX1\ 3O (:0

(cim r-C 0 o R C (CIIZ) CIIJI .u u XXV C:(. Cllz (CII2)7-COOR u oum cm I on n\ n' XXVI no [CHI (anal-000R I 11 o c112c113 In formulas II to XXIX, R is hydrogen, alkyl of one to 8 carbon atoms, inclusive, or a pharmacologically acceptable cation. In formula II and IV, 11 is 4 or 5. In formulas II and V, m is 7 or 8. In formulas VI and VIII, a is one or 2. In formulas VII and IX, b is 4 or 5. In formulas X and XIV, d is 7 'or 8 and p is one, 2, or 3. In formulas XI and XV, e is 3, 4, or 5. In formulas XVIII and XXIV,fis 4, 5 or 6 and q is one, 2', or 3. In formulas XIX and XXV, t is one or 2. In formulas XXII and XXVIII, v is'one or 2.

Compounds of formula I wherein indicates an alpha attachment of hydroxy to the ring are analogs of prostaglandin F (PGF, when a is zero and are analogs of prostaglandin F (IPGF a when a is one. Compounds of formula 1 wherein indicates a beta attachment of hydroxy to the ring are analogs of prostaglandin F (PGF p when a is zero and are analogs of prostaglandin F 5 (lPGF when a is one.

PGF a has the following structure:

(I O OH no" XXXI XXXll no 11 on PGF B has the following structure:

Molecules of PGF, PGE, B PGF a and PGF B and of each of the compounds encompassed by formulas l-XXIX each have several centers of asymmetry. Formulas l-XXlX are intended to represent o'ptically active compounds each with the same absolute configuration as optically active PGF, obtained from certain mammalian tissues, for example, sheep vesicular glands or human seminal plasma. See, for example, Bergstrom etal., Pharmacol. Rev. 20, l (1968) and references cited therein.

in formulas l-XXXlIl broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the-cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i,e., above the plane of the cyclopentane ring. The configuration of the side chain hydroxy in each formula is S, as also specified in the above systematic name for PGF See Nature, 212, 38 (1966) for discussion of the seereochemistry of the prostaglandins.

Each ofthe known prostaglandins PGF PGF PGF a and PGF B have carbon atoms. A significant characteristic of these known prostaglandins is the seven carbon carboxyl-terminated side chain. Prostaglandins obtained from animal tissues always contain that length of that chain. In contrast, each of the novel prostaglandin analogs encompassed by formulas l-XXIX, exclusive of the possible carbon content of R, have a carboxyl-terminated chain shorter or longer than seven carbon atoms. Some of the novel compounds ofthis invention have the same total nu er of carbon atoms present in the known prostaglandins, while some have fewer and some have more carbon atoms, but in each novel compound, the carboxylterminated chain is different than in the known prostaglandins. It will be observed that compounds of formulas ll-lX each have the same methyl-terminated chain present in the known prostaglandins. Both the methylterminated chain and the carboxyl-terminated chain in compounds of formulas XXXIX differ from those chains in the natural prostaglandins.

' PGF, a PGF a PGF, ,3 and PGF B .and their esters and pharmacologically acceptable salts, are extremely potent in causi pg various biological-responses.

For that reason, these compounds are useful for pharmacological'purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. A few of those biological responses are systemic arterial blood pressure lowering in the case of the PGF 3 compounds as measured, for example, in anesthetized (pentobarbital sodium) pentoliniumtreated rats with indwelling aortic and right heart cannulas; pressor activity, similarly measured, for the POP compounds; stimulation of smooth muscle as shown, for example, by tests on strips of quinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; activity on the central ner vous system; decrease of blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and inhibitionof blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen.

Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in .birds and mammals, includ- 1 ing humans, useful domestic animals, pets and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.

For example, these compounds are useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a dose range of about 10 ug. to about 10 mg. per ml. ofa pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

The PGF and PGF compounds are useful in the treatment of asthma. For example, these compounds are useful as bronchodilators or as inhibitors of mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, brochiectasis, pneumonia and emphysema. For these purposes, these compounds are administered in a variety of dosage forms, e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenterally, subcutaneously, or intramuscularly, with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder. Doses in the range of about 0.01 to 5 mg. per kg. of body weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency and route of administration. For the above use these prostaglandins can be combined advantageously with other anti-asthmatic agents, such as sympathominetics (isoproterenol, phenylephrine, ephedrine, etc.)', xanthine derivatives (theophylline and aminophyllin); and cortico-steroids (ACTH and predinisolone). Regarding use of these compounds see South African Pat. No. 681,055.

The PGF and PGF ,3 compounds are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals,- including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent postoperative thrombosis, to promote patency of vascular the range of 0.004 to about 20 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The PGF (1 and PGF [3 compounds are especially useful as additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extra-corporeal circulation and perfusion ofisolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or pre' pared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the

compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady-state dose of about 0.001 to 10 mg. per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.

The PGF [3 compounds are useful as hypotensive agents to reduce blood pressure in mammals, including man. For this purpose, the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 pg. per kg. of body weight per minute or in single or multiple doses of about 25 to 500 pg. per kg. of body weight total per day.

The PGF B compounds also increase the flow of blood in the mammalian kidney, thereby increasing volume and electrolyte content of the urine. Therefore, these compounds are useful in managing cases of renal disfunction, especially those involving blockage of the renal vascular bed. Illustratively, the compounds are useful to alleviate and correct cases of edema resulting, for example, from massive surface burns, and in the management of shock. For these purposes, the compounds are preferably first administered by intravenous injection at a dose in the range 10 to 1000 pg. per kg. of body weight or by intravenous infusion at a dose in the range 0.1 to peg. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, intramuscular, or subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of body weight per day.

The PGF a and PGF 5 compounds are useful in place of oxytocin to induce labor in pregant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about 20 Weeks to term. For this purpose, the compound is infused intravenously at a dose 0.01 to 50 ug. per kg. of body weight per minute until or near the termination of the second stage of labor,

10 i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started.

The PGF 0, and PGF [3 compounds are useful for controlling the reproductive cycle in ovulating female mammals, includinghumans and animals such as monkeys, rats, rabbits, dogs, cattle, and the like. For that purpose, PGF a for example, is administered systemically at a dose level in the range 0.0] mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Additionally, expulsion of an embryo or a fetus is accomplished by similar administration of the compound during the first third of the normal mammalian gestation period.

The novel PGF a and PGF 3 analogs encompassed by formulas I-XXIX each cause the same biological respouses described above for the corresponding known prostaglandins. Each of these new compounds is accordingly useful for the above-described pharmacological purposes, and is used for those purposes in. the same manner as described above.

The known PGF 0 and PGF 5 compounds'are all potent in causing multiple biological responses even at low doses. For example, PGF; 3 stimulates smooth muscle and also lowers blood pressure at the same low dose. Moveover, for many applications, these known prostaglandins havean inconveniently short duration of biological activity. In striking contrast, the novel Formula l-XXIX compounds are substantially more specific with regard to potency in causing prostaglandin-like biological responses, and have a substantially longer duration of biological activity. Therefore, each of these novel prostaglandin analogs is surprisingly and unexpectedly more useful than one of the corresponding above-mentioned known prostaglandins for at least one of the pharmacological purposes indicated above for the latter, because it has a different and narrower spectrum of biological activity than the known prostaglandins, and therefore is more specific in its activity and causes smaller and fewer undesired side effects than when the known prostag landin is used for the.

same purpose. Moreover, because of its piolonged activity, fewer and smaller doses of the novel prostaglandin analog can frequently be used to attain the desired result.

Another advantage of the novel compounds of this invention is that they are administered effectively orally, sublingually, intravaginally, buccally, or rectally, in addition to the usual intravenous, intramuscular, or subcutaneous injection or infusion methods indicated above for the uses of the known p'rostaglandins. These qualities are advantageous because they facilitate maintaining uniform levels of these compounds in the body with fewer, shorter, or smaller doses, and make possible self-administration by the patient.

The novel PGF (1 and PGF 5 compounds encompassed by formulas l-XXIX are used as described above in the free acid form, in alkyl ester form, or in pharmacologically acceptable salt form. When the ester form is used, any alkyl ester can be used wherein the alkyl moiety contains one to 8 carbon atoms, inolusive, i.e., methyl, ethyl, propyl, butyl, pentyl, hexyl,

heptyl, octyl, and isomeric forms thereof. However, it is preferred that the ester be alkyl of one to four carbon atoms, inclusive. Of those alkyl, methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system.

Pharmacologically acceptable salts of these formula l-XXlX compounds useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkali metals, elg., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary, or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, 'dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine, ,B-phenylethylamine, ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic, and araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., l-methylpiperidine, 4- ethylmorpholine, l-isopropylpyrrolidine, 2- methylpyrrolidine, 1,4-dimethylpiperazine, 2-

methylpiperidine, and the like, as well as amines containing watersolubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-l-butanol, 2-amino-2- ethyl-1,3-propanediol, '2-amino-2-methyl-l-propanol, tris(hydroxymethyl)aminomethane, N- phenylethanolamine, N-(ptert-amylphenyl)diethanolamine, galactamine, N-methylglucamine, N- methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like.

As discussed above, the compounds of formulas l-XXIX are administered in various ways for various purposes; e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, buccally, sublingually, topically, and in the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For that purpose, it is preferred because of increased water solubility to use the free acid form or the pharmacologically acceptable salt form. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt, or ester form in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceutical carriers are used for oral or sublingual administra tion. For rectal or vaginal administration, suppositories prepared as known in the art are used. For tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used.

It is known to prepare PGF, and PGF, 3 by carbonyl reduction of the prostaglandin known as PGE Similarly, PGF a and PGF B are prepared by carbonyl reduction of PGE PGE has the following structure:

no 11 on PGE; has the following structure:

In the same manner, each of the novel PGF (1 and PGF' 3 acid and ester analogs of formulas l-XXIX is prepared by carbonyl reduction of the corresponding PGE analog. Each such reduction gives a mixture of the corresponding PGF and PGF [3 compounds.

These ring carbonyl reductions are carried out by methods known in the art for ring carbonyl reductions of known prostaglandins. See, for example, Bergstrom et al., Arkiv Kemi 19, 563 (1963), Acta Chem. Scand. 16, 969 (1962), and British Specification No. 1,097,553. Any reducing agent is used which does not react with carbon-carbon double bonds or ester groups. Preferred reagents are lithium (tri-tertbutoxy) aluminum hydride, the metal borohydrides, especially sodium potassium and zinc borohydrides, and the metal trialkoxy borohydrides, e.g., sodium trimethoxyborohydride. The mixtures of alpha and beta hydroxy reduction products are separated into the individual alpha and beta isomers by methods known in the art for the separation of analogous pairs of known isomeric prostaglandins. See, for example, Bergstrom et al., cited above, Granstrom et al., J. Biol. Chem. 240, 457 (1965), and Green et al., J. Lipid Research 5, 117 1964). Especially preferred as separation methods are partition chromatographic procedures, both normal and reversed phase, preparative thin layer chromatography, and coun tercurrent distribution procedures.

Some of the PGE, and PGE type reactants needed for these carbonyl reductions are known in the art. See, for example, Struijk et al., Rec. Trav. Chim. 85, 1233 1966). The other necessary PGE, and PGE type reactants are prepared by the process described in our copending application Ser. No. 345,852, filed Feb. 19, 1964, now US. Pat. No. 3,296,091. See also Kupiecki, Life Sciences 4, 1811 (1965), Struijk, cited above, and Nugteren et al., Rec. Trav. Chim. 85, 405 (1966).

The process of our said US. Pat. No. 3,296,091 comprises aerobic incubation of various all-cis trienoic acids and tetraenoic acids of the same carbon content desired in the PGE type product with comminuted mammalian gland tissue or with the enzyme system contained therein, in a substantially aqueous medium. Sheep vesicular glands are especially preferred as tissues for thisprocess. As indicated in that patent, the trienoic or tetraenoic acid is cyclized and oxygenated by this process to give the desired PGE type compound. For example, use of all-cis 9,12,15-docosatrienoic acid thereby yields 8-l3a-hydroxy-2B-(3Shydroxy-trans-1- nonenyl)-5-oxo-cyclopent-1a-yl]octanoic acid.

The same process of our said U.S. Pat. No. 3,296,091 also produces some of the PGF type compound corresponding to the PGE type compound. For example, use of all-cis 9,12,15-docosatrienoic acid gives not only the PGE type analog mentioned above but also the corresponding PGF type compound, i.e., 8-[3oz,50zdihydroxy-2B-(3s-hydroxy-trans'l-noneyl)-cyclopentla-ylloctanoic acid. This mixture of PGE type and PGF type products is separated, and each component is purified, both by the procedures set forth in said patent, or by other procedures known in the art to be useful for separating mixtures of the known prostaglandins and purifying the individual compounds. In partic ular, advantage is taken of the greater polarity of the PGF type compound in comparison with the PGE type compound in these separations, using chromatography on acid washed silica gel, reversed phase partition chromatography, preparative thin layer chromatography, or countercurrent distribution, or a combination of those. Thus, this enzymatic conversion of all-cis trienoic and tetraenoic acids provides a second route to the novel PGF a analogs of this invention.

All-cis trienoic and tetraenoic acids necessary to produce the PGE type compounds corresponcind to the PGE type compounds of formula 1 are encompassed by the formula:

CH (CH ),,,(CH=CHCH ),.(CH ),,COOH wherein m is one, 2, 3, 4, or as defined above, x is 3 or4 (a 3), andy is one, 2, 3, 4, 5, 6, or 7 (n l), a and n being as defined above. All-cis acids of that formula are known in the art, or are prepared by methods known in the art, for example, by the method of Osbond et al., Chem. 1nd. (London) 1288 (1959) and J. Chem. Soc. (London) 2779 (1961 the necessary intermediate acetylenic alcohols being prepared by the method ofConia, Bull. Soc. Chim. France 22 [5], 1449 (1955), and transformed to the corresponding substituted propargyl bromides by reaction with phosphorus tribromide. See also van der Streen et al., Rec. Trav. Chem. 82, 1015 (1963).

Since our invention of the novel compounds of formulas 1XXIX, other methods have become available for making PGE PGE PGF, a and PGF; These methods can easily be adapted to make the novel PGF analogs of this invention or to make the PGE intermediates necessary for preparation of the novel PGF a and PGF [3 analogs of this invention by car bonyl reduction. See, for example, Corey et al., J. Am. Chem. Soc. 91, 535 (1969); ibid., 92, 397 (1970); ibid., 92, 2586 (1970). In each case, the adaptation consists of the use of the appropriately different reactant to introduce the desired carboxyl-terminated chain and, for the compounds of formulas X-XXIX, the use of the appropriately different reactant to introduce the desired methyl-terminated chain. Otherwise, the procedures and reactants are the same as used by Corey et al.

The alkyl ester forms of the novel PGF analogs of this invention are prepared either by esterification of the corresponding PGF type ester intermediate. Esterification of the PGF type free acid or the PGE type free acid reactant is advantageously accomplished by interaction of said free acid with the appropriate diazohydrocarbon. For example, when diazomethane is used, the methyl esters are produced. Similar use of diazoethane, diazobutane. and l-diazo-2 -ethylhexane, for example, gives the ethyl, butyl, and 2-ethylhexyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid reactant, advantageously in the same or a different inert diluent. After the esterification reaction is complete, the solvent is removed by evaporation, and the ester purified if desired by conventional methods, preferably by chromatography. It is preferred that contact of the acid reactants with the diazohydrocarbon be no longer than necessary to effect the desired esterification, preferably about one to about ten minutes, to avoid undesired molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art. See, for example, Organic Reactions, John Wiley & Sons, Inc., New York, NY. Vol. 8, pp. 389-394 (1954).

An alternative method for esterification of the carboxy] moiety of the PGE-type compound or PGEtype reactant comprises transformation of the free acid to the corresponding silver salt, followed by interaction of that salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tertbutyl iodide, and the like; The silver salts are prepared by conventional methods, for example, by dissolving the acid in cold dilute aqueous am-.

monia, evaporating the excess ammonia at reduced pressure, and then adding the stoichiometric amount of silver nitrate.

The novel formula I PGF type free acids are transformed to pharmacologically acceptable salts by neutralization with appropriate amounts of the corresponding inorganic or organic base, examples of which correspond to the cations and amines listed above. These transformations are carried out by a variety of procedures known in the art to be generally useful for the preparation of inorganic, i.e., metal or ammonium, salts, amine acid addition salts, and quaternary ammo nium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salt to be prepared. 1n the case of the inorganic salts, it is usually suitable to dissolve the acid in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt of the prostanoic acid derivative.

Evaporation of the water or addition of a watermiscible solvent of moderate polarity, for example, a lower alkanol or a'lower alkanone, gives the solid inorganic salt if that form is desired.

To produce an amine salt, acid is dissolved in a suit able solvent of either moderate or low polarity. Examples of the former are ethanol, acetone, and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it is usually obtained in solid form by addition of a miscible diluent of low polarity or by evaporation. If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use stoichiometric amounts of the less volatile amines.

EXAMPLE 1 8-[ 3 01,5 a-dihydroxy-2B-( 3S-hydroxy-trans- 1 noneny)cyclopent-1a-yl]octanoic acid and 8-[3a,5B- dihydroxy-2/3-( 3S-hydroxy-trans- 1 -nonenyl )cyclopent-la-ylloctanoic acid. (Formula I: a O, n 7, m

"A solution of sodium borohydride (0.30 g.) in 1 ml. of water is added with stirring to a solution of 8-[30zhydroxy-2B-(3S-hydroxy-trans-l-nonenyl)-5-oxo cyclopent-1a-yl]-octanoic acid (600 mg.) in 25 ml. of absolute ethanol at C. The mixture is stirred 2.5 hours-at 0 C. Then, 15 ml. of acetone is added and, minutes later, 3 volumes of water is added. The mixture is acidified with dilutehydrochloric acid and then extractedwith dichloromethane. The extract is washed with saturated aqueous sodium chloride solution, dried, and evaporated. The residue is chromatographed on silica gel, eluting with chloroform containing percent absolute ethanol. The eluate fractions containing the PGF type and PGF B type compounds as shown by thin layer chromatography are separately combined and evaporated to give, respectively, 8-[3a,5adihydroxy-2B-( 3S-hydroxy-transl -nonenyl )-cyclopent-la-yHoctanoic acid and 8-[3a,5B -dihydroxy-2fi- (3S-hydroxy-trans-l-nonenyl)-cyclopent-1ayl]octanoic acid.

Following the procedure-of Example 1, the methyl,

ethyl, and octyl esters of the same PGE type acid is transformed to the methyl, ethyl, and octyl esters of the same PGF, type and PGF B type acids.

Also following the procedure of Example 1, the free acid form and the methyl, ethyl, and octyl ester forms of the following PGF a type and PGF ,3 type compounds are each produced by carbonyl reduction of the corresponding PGE type free acids and methyl esters, reference being made to the various parameters of formula 1:

Example No. a n m 9 l 4 4 I0 I 5 4 l l l 2 5 12 l 7 I l3 1 5 l l4 I I 4 l5 0 5 3 16 l 2 3 I7 I 4 5 EXAMPLE l8 8-[ 3rx-hydroxy-2B-( 3S-hydroxy-transl -nonenyl 5-oxo-cyclopent-la-yl]octanoic acid.

The procedure of Example 1 of our said US. Pat. No. 3,296,091 is followed, but in place of the arachidonic acid reactant specified therein, there is used all-cis 9,12,15-docosatrienoic acid. A mixture of 8-[3ahydroxy-2B-(3-S-hydroxy-transl nonenyl)-5-oxocyclopent- 1 a-yl ]octanoic acid and 8-[ 3a,5adihydroxy-2,B-(3S-hydroxy-trans-1-nonenyl)-cyclopent-1a-yl]octanoic acid is produced and isolated as described in said patent. The components of this mixture are separated by silica gel chromatography and purified as described by Samuelsson, J, Biol. Chem. 238, 3229 (1963) for the separation and purification of PGE and PGFm.

Following the procedure of Example 18, each of the PGE-type reactants used to prepared the PGF..-type .and PGF -type products of Example 2-18 is pre pared from the corresponding all-cis trienoic or tetraenoic acid.

We claim:

1. A compound of the formula:

wherein R is hydrogen, alkyl of one to 8 carbon atoms, or a pharmacologically acceptable cation.

2. A compound according to claim 1 wherein R is hy- 

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 wherein R is hydrogen. 